Project Summary Traumatic knee injury is common and highly debilitating. Surgical reconstruction/repair improves knee biomechanics and function, but neuromuscular dysfunction persist for years despite rehabilitation, hindering resumption of normal activities, increasing risk of further injury and, in a majority of patients, hastening the development of knee osteoarthritis (OA). The period from the injury through the early, post-surgical period is critical for the development of functional deficits, as the trauma of the injury and surgery combine with muscle disuse to reduce skeletal muscle size and intrinsic function. Rehabilitative interventions seek to remediate these deficits following post-surgical recovery, but they are only marginally successful. Rather than attempt to correct these adaptations once they have occurred, the proposed studies are designed to evaluate a more proactive approach that seeks to prevent these adaptations. Our goal is to evaluate the utility of neuromuscular electrical stimulation (NMES), initiated following injury and maintained through the early post- surgical period, to prevent muscle atrophy and intrinsic contractile dysfunction. Our rationale is that early intervention and prevention of these muscle adaptations will lead to improved muscle function and, over the longer-term, a reduced risk for further injury and the development of OA, as well as improved patient-reported outcomes and satisfaction with treatment. While NMES is used clinically to enhance neural activation and contractile responses to strengthening exercises during standard rehabilitation, its utility as a singular modality during the post-injury and early, post-surgical period to prevent intrinsic muscle morphological and functional adaptations has never been evaluated. Based on our preliminary data, we hypothesize that early institution of NMES will prevent or diminish skeletal muscle fiber atrophy and contractile dysfunction and, in turn, improve whole muscle function at short-term follow-up. To address this hypothesis, patients with traumatic knee injury will be randomized to our current standard of care rehabilitation or rehabilitation plus early use of NMES, with measurements of skeletal muscle structure and function at the whole body, tissue and cellular levels, as well as patient-reported outcomes. If our hypotheses are correct, our results will provide mechanistic evidence supporting an effect of NMES to maintain muscle size and function following knee joint injury and surgical treatment, which would provide proof-of-principle evidence to support a more proactive, preventative approach to rehabilitation of these patients. We plan to carry this work forward into a randomized, controlled trial that combines early NMES with our recently described accelerated, post-surgical rehabilitation program to more effectively prevent and rehabilitate skeletal muscle morphological and functional deficits following traumatic knee injury and treatment, with the long-term goal of preventing subsequent joint pathology and improving clinical and patient-reported outcomes.